Modeling the stimulatory network of CD16, 2B4 and NKG2D in natural killer cell activation

Abstract

Natural killer (NK) cells are innate immune effector cells that play an immediate role in host defense by releasing cytotoxic chemicals upon activation. A better understanding of the mechanisms regulating NK cell activation can improve NK cell-based therapies. However, due to the diversity of stimulatory pathways, each with a complex network of signaling species, a systems biology approach is required to understand NK cell activation. We constructed a mathematical model that mechanistically describes the signaling network of CD16, 2B4 and NKG2D. The model was fit to published experimental data and validated with a separate dataset. Baseline model predictions demonstrate that CD16 and NKG2D are qualitatively similar in that they activate the downstream species to a greater degree and at a faster rate when compared to 2B4. Contrastingly, 2B4 activates the signaling species over a longer time interval. In silico pairwise co-stimulation of the receptors, using various ligand concentrations, preferentially impacts the kinetics of species activation: the species are activated faster but the time interval of species activation becomes shorter as more ligands are introduced. Perturbing the stimulatory pathways by altering kinase (activator) and phosphatase (inhibitor) activity, highlights the phosphatases’ predominant control of the network and shows that decreasing their level of activity greatly improves the rate of species activation. Thus, the model predicts (1) qualitative differences between the pathways, (2) increasing receptor stimulation impacts the kinetics of species activation and (3) inhibiting the inhibitor significantly augments signal transduction. This insight can help design NK cell immunotherapies.